Clofazimine Inhalation for Nontuberculous Mycobacterial Infections
(ICoN-1 Trial)
Recruiting in Palo Alto (17 mi)
+48 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Mannkind Corporation
Must be taking: Guideline-based therapy
Must not be taking: Amikacin, Bedaquiline, Prednisone
Disqualifiers: Cystic fibrosis, Active tuberculosis, others
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 4 Jurisdictions
Trial Summary
What is the purpose of this trial?This clinical trial is designed to compare the efficacy and safety of Clofazimine Inhalation Suspension versus placebo when added to guideline-based therapy (GBT)
Will I have to stop taking my current medications?
The trial requires participants to have been on a stable multi-drug regimen for their lung infection for at least 6 months before joining, with no changes in the last 2 months. This suggests you should continue your current medications as long as they meet these criteria.
What data supports the effectiveness of the drug Clofazimine Inhalation Suspension for treating nontuberculous mycobacterial infections?
Research shows that clofazimine has strong activity against nontuberculous mycobacteria in lab studies, and an inhaled form of the drug demonstrated promising results in animal studies by maintaining high levels in lung tissue, which could help treat lung infections effectively while reducing side effects.
12345Is clofazimine inhalation safe for humans?
Clofazimine inhalation has been studied in animals and shows promise in reducing toxicity compared to oral forms, as it delivers the drug directly to the lungs, minimizing systemic exposure. While these studies suggest it may be safer, more research in humans is needed to confirm its safety.
12678What makes Clofazimine Inhalation Suspension unique for treating nontuberculous mycobacterial infections?
Clofazimine Inhalation Suspension is unique because it is administered through inhalation, which directly targets the lungs where nontuberculous mycobacterial infections often occur, potentially increasing its effectiveness compared to traditional oral or intravenous routes.
234910Eligibility Criteria
Adults aged 18-85 with lung disease caused by Mycobacterium Avium Complex (MAC), who are already on a multi-drug regimen for at least 6 months, can produce sputum samples, and have no recent use of certain drugs or conditions like active cancer. Women must not be pregnant and agree to contraception; men must also agree to contraception if they can father children.Inclusion Criteria
FEV1 ≥40% of predicted during screening
I can produce the required amount of sputum for the test.
I have been on a specific treatment for NTM lung infection for at least 6 months without changes.
+7 more
Exclusion Criteria
Inability to inhale with a nebulizer, in the opinion of the investigator
Known hypersensitivity to any of the ingredients or excipients of clofazimine
I haven't had cancer treatments in the last 3 years and don't expect any during the study.
+22 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment (Part A)
Participants receive Clofazimine Inhalation Suspension or placebo daily for 28 days in Cycle 1, followed by 56 days off treatment, and then resume daily for 28 days in Cycle 2
6 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Open-label extension (Part B)
Qualified participants receive Clofazimine Inhalation Suspension from Study Month 7 through Study Month 22
16 months
Participant Groups
The trial is testing the effectiveness and safety of Clofazimine Inhalation Suspension compared to a placebo in patients with MAC lung disease. Participants will continue their current drug regimens alongside the trial medication or placebo.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Clofazimine Inhalation SuspensionExperimental Treatment1 Intervention
MNKD-101 (Clofazimine Inhalation Suspension) is a micronized suspension with a concentration of 20 mg/mL. Study drug will be inhaled using the PARI breath-enhanced jet nebulizer system daily for 28 days in Cycle 1. Cycle 2 will commence after 56 days off treatment and resume daily for 28 days. Dose: 80 mg
Group II: PlaceboPlacebo Group1 Intervention
The placebo is comprised of isotonic saline (0.9% weight/volume sodium chloride). Study drug will be inhaled using the PARI breath-enhanced jet nebulizer system daily for 28 days in Cycle 1. Cycle 2 will commence after 56 days off treatment and resume daily for 28 days.
Clofazimine Inhalation Suspension is already approved in United States, Japan, Australia for the following indications:
🇺🇸 Approved in United States as MNKD-101 for:
- Nontuberculous mycobacterial (NTM) lung disease
🇯🇵 Approved in Japan as MNKD-101 for:
- Nontuberculous mycobacterial (NTM) lung disease
🇦🇺 Approved in Australia as MNKD-101 for:
- Nontuberculous mycobacterial (NTM) lung disease
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Stanford UniversityStanford, CA
St. Francis Sleep, Allergy & Lung InstituteClearwater, FL
Theia Clinical ResearchSaint Petersburg, FL
Infectious Diseases Consultants of the Treasure CoastSebastian, FL
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Mannkind CorporationLead Sponsor
References
Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection. [2023]Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.
In vitro activity of clofazimine against rapidly growing nonchromogenic mycobacteria. [2021]The in vitro activity of clofazimine against 80 isolates of rapidly growing nonchromogenic mycobacteria was studied by an agar dilution method. The drug inhibited 96% of strains tested at concentrations less than or equal to 1 microgram/ml, and it appears to be an agent of potential efficacy against Mycobacterium fortuitum and M. chelonae.
Novel Administration of Clofazimine for the Treatment of Mycobacterium avium Infection. [2022]Clofazimine has demonstrated in vitro activity against many nontuberculous mycobacteria. We present the case of a woman with cystic fibrosis who developed disseminated macrolide-resistant Mycobacterium avium infection following lung transplantation treated in part with clofazimine. We describe the novel administration of clofazimine via gastrostomy tube.
Minimal Inhibitory Concentration of Clofazimine Among Clinical Isolates of Nontuberculous Mycobacteria and Its Impact on Treatment Outcome. [2021]Clofazimine has been regarded as a promising agent for the treatment of nontuberculous mycobacteria pulmonary disease (NTM-PD). However, its overall effectiveness in vitro and in the clinic remains unknown.
Synergistic Activity of Clofazimine and Clarithromycin in an Aerosol Mouse Model of Mycobacterium avium Infection. [2021]Infections with nontuberculous mycobacteria (NTM) have a poor prognosis in patients with underlying respiratory diseases. Clofazimine (CFZ) showed both experimental and clinical promising results against clinically relevant NTM. However, there are no data on CFZ in combination with the current recommended treatment; therefore, we aimed to study its in vivo activity in an aerosol mouse model of Mycobacterium avium In an aerosol infection BALB/c mouse model using M. avium strain Chester, we treated 58 mice with four combinations of rifampin (RIF) at 10 mg/kg, CFZ at 25 mg/kg, and clarithromycin (CLR) and ethambutol (EMB) at 100 mg/kg. Treatment efficacy was assessed on the basis of lung CFU counts after 2 (M2) and 4 (M4) months of treatment. At M2, CLR-RIF-EMB was slightly but significantly more efficient than CFZ-RIF-EMB (3.02 ± 0.12 versus 3.55 ± 0.28, respectively, P < 0.01), whereas CLR-CFZ-EMB and CLR-CFZ-RIF-EMB dramatically decreased lung CFU counts by 4.32 and 4.47 log10, respectively, compared to untreated group. At M4, CLR-RIF-EMB was significantly more efficient than CFZ-RIF-EMB (2 ± 0.53 versus 2.66 ± 0.22, respectively, P = 0.01). The addition of CLZ to CLR dramatically decreased the lung CFU count, with CFU counts 5.41 and 5.79 log10 lower in the CLR-CFZ-EMB and CLR-CFZ-RIF-EMB groups, respectively, than in the untreated group. The addition of CFZ to CLR seems to improve the efficacy of CLR as early as M2 and was confirmed at M4. CFZ, in addition to RIF and EMB, on the other hand, is less effective than CLR-RIF-EMB. These results need to be confirmed by similar studies along with CFZ potential for shortening treatment.
Respirable Clofazimine Particles Produced by Air Jet Milling Technique Are Efficacious in Treatment of BALB/c Mice with Chronic Mycobacterium tuberculosis Infection. [2023]Tuberculosis (TB) remains a major cause of morbidity and mortality, particularly in low- and middle-income countries where access to health care workers, cold-chain storage, and sterile water sources may be limited. Inhaled drug delivery is a promising alternative to systemic delivery of antimycobacterial drugs, as it enables rapid achievement of high infection-site drug concentrations. The off-patent drug clofazimine (CFZ) may be particularly suitable for this route, given its known systemic toxicities. In this study, micronized CFZ particles produced by air jet milling were assessed for shelf-stability, pharmacokinetics, and anti-TB efficacy by the oral and pulmonary routes in BALB/c mice. Intratracheal instillation of micronized CFZ particles produced several-fold higher lung concentrations after a single 30 mg/kg dose compared to delivery via oral gavage, and faster onset of bactericidal activity was observed in lungs of mice with chronic Mycobacterium tuberculosis infection compared to the oral route. Both infection status and administration route affected the multidose pharmacokinetics (PK) of micronized CFZ. Increased lung and spleen accumulation of the drug after pulmonary administration was noted in infected mice compared to naive mice, while the opposite trend was noted in the oral dosing groups. The infection-dependent PK of inhaled micronized CFZ may point to a role of macrophage trafficking in drug distribution, given the intracellular-targeting nature of the formulation. Lastly, air jet milled CFZ exhibited robustness to storage-induced chemical degradation and changes in aerosol performance, thereby indicating the suitability of the formulation for treatment of TB in regions with limited cold chain supply.
Antimycobacterial activity of some potential chemotherapeutic compounds. [2019]Fourteen compounds were tested in vitro for activity against Mycobacterium intracellulare and other pathogenic mycobacteria. Only clofazimine and chaulmoogric acid showed significant activity against M. intracellulare. In view of known minimal side effects of clofazimine further studies are warranted for this drug in chemotherapy of M. intracellulare infections.
Clofazimine as a comparator for preclinical efficacy evaluations of experimental therapeutics against pulmonary M. abscessus infection in mice. [2023]Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) can cause chronic pulmonary disease in the setting of structural lung conditions. Current treatment recommendations require at least one year of daily therapy with repurposed antibiotics. Yet these therapies are often ineffective and associated with significant adverse events. To address this challenge, research efforts are underway to develop new antibiotics and regimens. During the preclinical phase of treatment development, experimental agents require testing and comparison alongside positive controls that are known agents with clinical history. As there are no FDA approved treatments for this indication, here, we have considered repurposed antibiotics currently included in the recommendation for treating Mab disease as candidates for selection of an ideal standard comparator that can serve as a positive control in preclinical studies. Clofazimine meets the criteria for an ideal positive control as it can be administered via the least invasive route, requires only once-daily dosing, is well tolerated, and is widely available in high purity from independent sources. Using a mouse model of pulmonary Mab disease, we assessed for ideal dosages of clofazimine in C3HeB/FeJ and BALB/c mice in a six-week treatment window. Clofazimine, 25 mg/kg, once daily, produced desired reduction in Mab burden in the lungs of C3HeB/FeJ and BALB/c mice. Based on these findings, we conclude that clofazimine meets the criteria for a positive control comparator in mice for use in preclinical efficacy assessments of agents for treatment of Mab pulmonary disease. Although not included in the current standard-of-care for treating Mab disease, rifabutin, 20 mg/kg, also produced desired reduction in Mab lung burden in C3HeB/FeJ mice but not in BALB/c mice. IMPORTANCE: Mycobacteroides abscessus can cause life-threatening infections in patients with chronic lung conditions. New treatments are needed as cure rate using existing drugs is low. During pre-clinical phase of treatment development, it is important to compare the efficacy of the experimental drug against existing ones with known history. Here, we demonstrate that clofazimine, one of the antibiotics repurposed for treating Mab disease, can serve as a positive control comparator for efficacy assessments of experimental drugs and regimens to treat M. abscessus disease in mice.
Safety and Effectiveness of Clofazimine for Primary and Refractory Nontuberculous Mycobacterial Infection. [2018]Clofazimine is an antimicrobial agent that has activity in vitro against mycobacteria. Increasingly, it has been used for the treatment of nontuberculous mycobacteria (NTM), despite limited data supporting its use in this setting. The objective of this study was to evaluate the safety, tolerability, and clinical outcomes associated with clofazimine in patients with NTM infection.
Clofazimine for treatment of multidrug-resistant non-tuberculous mycobacteria. [2021]/QUESTION: Nontuberculous mycobacteria (NTM) infections are increasingly detected but difficult to cure given complex drug-resistance patterns. Select U.S. centers have incorporated clofazimine in the treatment of NTM but experience is limited as procurement restrictions hamper widespread use.